Method for making a microsealed delivery device

ABSTRACT

The present invention is concerned with a pharmaceutical delivery device comprising a biologically acceptable silicone polymer matrix having microsealed compartments of 10-200 microns throughout, wherein the microsealed compartments contain a pharmaceutical in a hydrophilic solvent system. The biologically acceptable silicone polymer matrix is formed by in situ cross linking of a liquid, biologically acceptable silicone polymer in an emulsion of pharmaceutical in the hydrophilic solvent system and liquid biologically acceptable silicone polymer. The biologically acceptable silicone polymer matrix is placed in a sealed or unsealed biologically acceptable polymer container. The rate of release of pharmaceutical is controlled by altering the solubility characteristics of the hydrophilic solvent system and/or the biologically acceptable polymer matrix, the rate of release being independent of time when the ratio of the partition coefficient of the pharmaceutical between the hydrophilic solvent system and biologically acceptable silicone polymer matrix to the solubility of the pharmaceutical in the hydrophilic solvent system is between 1 and 10 -   4  ml/mcg.

This is a division of application Ser. No. 517,454, filed Oct. 24, 1974,now U.S. Pat. No. 3,946,106.

The present invention is concerned with a pharmaceutical delivery devicecomprising a biologically acceptable polymer container and an innerbiologically acceptable silicone polymer matrix contained within thebiologically acceptable polymer container, the inner biologicallyacceptable silicone polymer matrix having microsealed compartmentsthroughout, the microsealed compartments containing a pharmaceutical ina hydrophilic solvent system, wherein the ratio of the partitioncoefficient of the pharmaceutical between hydrophilic solvent system andthe inner biologically acceptable silicone polymer matrix to thesolubility of the pharmaceutical in hydrophilic solvent system isbetween 1 and 10.sup.⁻⁴ ml/mcg, the pharmaceutical being diffusablethrough the inner biologically acceptable silicone polymer matrix andbiologically acceptable polymer container at a therapeutically effectiveconstant rate when the microsealed pharmaceutical delivery device is inan aqueous environment, the hydrophilic solvent system beingnon-diffusable through the inner biologically acceptable siliconepolymer matrix and biologically acceptable polymer container.

Biologically acceptable polymer containers are containers adapted insize and shape for implanting in a body cavity or surgically under or onthe skin of an animal in need of prolonged administration of apharmaceutical. For example, the biologically acceptable polymercontainers encompassed in this invention may be adapted to serve as avaginal or an intrauterine insert; it may be adapted as an opthalmicmedicinal delivery device for insertion in the narrow confines betweenthe eyeball and the ocular cavity; it may be surgically inserted forparenteral administration, and may be adapted for administration ofpharmaceuticals to the gastrointestinal tract. The biologicallyacceptable polymer container may be sealed or unsealed and in thislatter aspect is sharply distinguished from polymer membranessurrounding an inner polymer matrix described in U.S. Pat. No.3,710,795. For example, the container may be a length of flexiblebiologically acceptable polymer tubing which is sealed or unsealed andalso may have additional perforations in the wall of the tubing suchthat as much as 40% of the inner biologically acceptable siliconepolymer matrix is exposed.

Materials used to form the biologically acceptable polymer container arethose capable of forming thin walls or coatings through whichpharmaceuticals can pass at a controlled rate. Suitable polymers arebiologically and pharmaceutically compatible, non-allergenic, andinsoluble in and non-irritating to body fluids or tissues with which thedevice is contacted. The use of soluble polymers is to be avoided sincedissolution or erosion of the device would affect the release rate ofthe pharmaceutical release rate, as well as the capability of the deviceto remain in place for convenience of removal. Exemplary materials forfabricating the biologically acceptable polymer container includepolyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, especially the medical grade polydimethyl siloxanes,neoprene rubber, chlorinated polyethylene, polyvinyl chloride; vinylchloride copolymers with vinyl acetate, poly methacrylatepolymer(hydrogel), vinylidene chloride, ethylene, and propylene;polyethylene terephthalate; butyl rubber; epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer; ethylene/vinyl acetate/vinyl alcoholterpolymer; ethylene/vinyloxyethanol copolymer; and the like. For bestresults, the biologically acceptable polymer container should beselected from polymers of the above classes with glass transitiontemperatures below room temperature. The polymer may, but need notnecessarily, have a degree of crystallinity at room temperature.

Polymers especially preferred for fabricating the biologicallyacceptable polymer containers of this invention have the followingformula: ##STR1## wherein n is about 5000 and R is selected from thegroup comprising phenyl, lower alkyl, vinyl, or allyl. Suitable polymersfor fabricating biologically acceptable polymer containers are describedin U.S. Pat. Nos. 3,279,996 and 3,710,795 as well as in PlasticMaterials In Surgery by Block and Hastings Charles Thomas, Publisher,Springfield, Ill., 2nd Edition (1972). Desirable polymers arecharacterized but not limited to the following physical parameters:

    ______________________________________                                                           Test Value                                                 ______________________________________                                        Durometer Hardness(shore A)                                                                        45 to 70                                                 Tensil strength, psi 1100                                                     Elongation           500-700%                                                 Tear strength lbs./in.                                                                             120-160                                                  ______________________________________                                    

The inner biologically acceptable silicone polymer matrix is preferablyfabricated from room temperature cross-linked silicone rubber(polydimethylsiloxane)such as silicone polymers of the formula: ##STR2##wherein R is alkoxy containing 1-7 carbon atoms, vinyl or allyl andwherein n is about 100-5000.

A saturated solution of pharmaceutical in water and hydrophilic solventis dispersed throughout liquid silicone polymer by means of high speedstirring before cross-linking of the polymer. The polymer iscross-linked leaving microsealed compartments filled with hydrophilicsolvent--water--and pharmaceutical throughout the matrix. The matrix maybe constructed in situ in a preshaped biologically acceptable polymercontainer or the matrix may be preformed and coated with a polymermembrane which serves as a biologically acceptable polymer container.Methods of coating a matrix with biologically acceptable polymers aredescribed in U.S. Pat. No. 3,710,795. Desirable but not exclusivepolymers are characterized by the following physical parameters:

    ______________________________________                                        Durometer Hardness (Shore A)                                                                       45-100                                                   Tensil Strength      300-1400                                                 Elongation           100-300%                                                 Tear Strength        20-120 ppi                                               ______________________________________                                    

The hydrophilic solvent system serves to partition the pharmaceuticalbetween the microsealed compartments and the biologically acceptablesilicone polymer matrix. The hydrophilic solvent system must becompatible with the pharmaceutical and must not permeate the polymer orthe biologically acceptable silicone polymer container. The hydrophilicsolvent system of the present invention comprises water and watermiscible solvents which increase the aqueous solubility of thepharmaceutical. Glycols such as polyethylene glycol, propylene glycol,butylene glycol, glycerol formal, and glycofurol are suitable solventswith polyethylene glycol of molecular weight of about 400 beingpreferred. Amides such as dimethylacetamide andN-(β-hydroxyethyl)-lactamide, ethyl lactate, dioxolanes represent otherdesirable pharmaceutically compatible water miscible solvents. Ionic andneutral surface active agents in aqueous concentrations above thecritical micelle concentration are effective hydrophilic solventsystems. P. H. Elworthy, A. T. Florence, and C. B. Macfarlane,Solubilization by Surface Active Agents, Chapman and Hall, 1968 describethe use and selection of surface active agents in pharmaceuticalchemistry. Preferred surface active agents are exemplified by sodiumdodecyl sulfate, polysorbates, cetyl trimethylammonium bromide, andcetyl-pyridinium chloride.

Pharmaceuticals permeable through the biologically acceptable innersilicone polymer matrix and biologically acceptable polymer containerand meeting the earlier defined solubility requirement may beeffectively administered over a long period of time. Scheme Iillustrates the required solubility relationship between thepharmaceutical, the hydrophilic solvent system and biologicallyacceptable silicone polymer matrix.

    __________________________________________________________________________    Scheme I                                                                      __________________________________________________________________________                  Microsealed                                                     Crystalline                                                                          Dissolution                                                                          liquid Partition        Elution                                 Drug   Cl     Compartment                                                                          Kb    Polymer                                                                            Permeation                                                                          in                                                                 phase      Solution                                __________________________________________________________________________

Solubility of a pharmaceutical (Cl) is measured by constant shaking for24 hours an excess amount of powdered pharmaceutical in 10 ml. of ahydrophilic solvent system at 37° C. The solution is filtered and thecontent of the pharmaceutical is measured.

Partition coefficient K(b) is measured by immersing a known surface areaof biologically acceptable silicone polymer matrix material in asolution of the pharmaceutical in the hydrophilic solvent system withconstant shaking for 24 hours and then measuring the amount ofpharmaceutical remaining in the solvent system. ##EQU1## Ci = initialconcentration of pharmaceutical Cl = Equilibrium concentration ofpharmaceutical

Table I is illustrative of the relation between Cl, Kb, release rate,and kinetics of release of 17α-ethynyl-4-estrene-3β,17β-diol3,17-diacetate (ethynodiol diacetate) in a hydrophilic solvent system ofpolyethylene glycol having a molecular weight of about 400.

                                      Table I                                     __________________________________________________________________________                                    Rate of                                                                       Pharma-                                       Microsealed                                                                           Pharmaceutical          ceutical                                      Liquid Com-                                                                           Solubility                                                                             Partition                                                                             Kb/Cl  Release                                       partments                                                                             (mcg/ml) Coefficient                                                                           (ml/mcg)                                                                             (gm/10.sup.6 cm.sup.2)                                                                Kinetics*                             __________________________________________________________________________    100% PEG 400                                                                          45600    0.032   7.0 × 10.sup.-.sup.7                                                           1095/day.sup.1/2                                                                      Q - t.sup.1/2                          80% PEG 400                                                                          4460     0.332   7.4 × 10.sup.-.sup.5                                                           1203/day.sup.1/2                                                                      Q - t.sup.1/2                          60% PEG 400                                                                          437      3.385   7.8 × 10.sup.-.sup.3                                                           319.4/day                                                                             Q - t                                  50% PEG 400                                                                          156      9.48    6.1 × 10.sup.-.sup.2                                                           315.6/day                                                                             Q - t                                  30% PEG 400                                                                          64.6     22.9    0.355  297.8/day                                                                             Q - t                                 __________________________________________________________________________     *Q - t.sup.1/2 relationship (matrix-controlled process) indicates that th     amount of pharmaceutical released decreases with time and Q - t               relationship (partition controlled process) indicates that a constant         amount of pharmaceutical is released independent of time.                

A wide variety of pharmaceuticals may be administered over a long periodof time. Steroids, alkaloids, fatty acids and lipid soluble vitamins aretypical pharmaceutical agents which may be incorporated into themicrosealed compartments of the present pharmaceutical delivery device.Representative pharmaceuticals which are advantageously administered bythe present delivery device are:

Estrogens: Mestranol, ethynyl estradiol, estrone, estradiol,estradiol-3-methyl ether diethylstilbestrol, and related estrogens andester derivatives thereof described at pages 423-429 in Cutting'sHandbook of Pharmacology, Appleton-Century-Crofts, New York, 1969.

Progestins: Progesterone, 17α-ethynyl-4-estrene-3β,17β -diol diacetate,17α-ethynel-11β-methyl- 4 estrene 3β, 17β-diol 3,17-diacetate,17α-acetoxy-11β-methyl-19-norpregn-4-en-3-one, and progestins listed onpages 420 to 436 in Cutting's Handbook of Pharmacology.

Androgens: Testosterone, testosterone propionate, testosteronephenylacetate and related androgens described in Cutting's Handbook ofPharmacology at pages 442 to 448.

Adrenal Cortical Hormones: Desoxycorticosterone acetate, prednisolone,and those described at pages 395 to 412 in Cutting's Handbook ofPharmacology.

Diuretics (Mineralcorticoid Blocking agents):7α-ethoxycarbonyl-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactone,17-hydroxy-7β-methoxycarbonyl-3-oxo-17γ-pregn-4-ene-21-carboxylic acidγ-lactone and diuretics described at page 241-243 of Cutting's Handbookof Pharmacology.

Vitamins: Vitamin E, vitamin K and derivatives thereof.

Anti-Protozoal Agents: Nitroimidazoles such as metronidazole.

Furthermore, simple derivatives of the pharmaceuticals (such as ethers,esters, amides, etc.) which have desirable polymer solubility andrelease characteristics, but which are easily hydrolyzed by body pH,enzymes, etc., can be employed.

The amount of drug incorporated in the drug-delivery device variesdepending on the particular drug, the desired therapeutic effect, andthe time span for which the device provides therapy. Since a variety ofdevices in a variety of sizes and shapes are intended to provide dosageregimens for therapy for a variety of maladies, there is no criticalupper limit in the amount of drug incorporated in the device. The lowerlimit, too, will depend on the activity of the drug and the time span ofits release from the device. Thus, it is not practical to define a rangefor the therapeutically effective amount of drug to be incorporated inor released by the device.

Those skilled in the pharmaceutical arts will know how to determinetoxic levels of a given pharmaceutical, and the minimum effective dose.With this information a proper dosage form can be prepared by measuringthe in vivo rate or elution of a given pharmaceutical by standardanayltic techniques e.g. spectroscopic or radio immunoassay analysis. Invitro diffusion of the pharmaceutical from a delivery device may bedetermined by the methods of Chien and Lambert, J. Pharm. Sci., 63, 365(1974) or by methods described in U.S. Pat. No. 3,710,795.

A preferred embodiment of the present invention is a microsealedpharmaceutical delivery device comprising a biologically acceptablepolymer container constructed of a molecularly oriented heat shrunk,stretched polymeric membrane having reserve elastic recovery stress, aninner biologically acceptable silicone polymer matrix of cross-linkedsilicone rubber wherein the biologically acceptable silastic polymermatrix has 10-200 micron microsealed compartments distributedthroughout, said microsealed compartment containing a pharmaceutical ina hydrophilic solvent system consisting of water and 20-70% polyethyleneglycol, said microsealed compartments being formed by in situcross-linking of the silicone rubber after it is mixed with thehydrophilic solvent system containing a pharmaceutical, thepharmaceutical being diffusible through the inner biologicallyacceptable silicone polymer matrix and biologically acceptable polymercontainer at a therapeutically effective constant rate when themicrosealed pharmaceutical delivery device is in an aqueous environment,said hydrophilic solvent being non-diffusible through the biologicallyacceptable silicone polymer matrix and biologically acceptable polymercontainer.

A most preferred embodiment of the present invention is a microsealedpharmaceutical delivery device comprising a biologically acceptablepolymer container constructed of silicone polymers of the formula##STR3## wherein n is about 5000 and R is phenyl, alkyl, vinyl or allylor polycarbonate copolymers thereof, an inner biologically acceptablesilicone polymer matrix constructed of cross-linked silicone polymer ofthe formula ##STR4## wherein R is alkoxy, alkyl, phenyl, vinyl or allyland wherein n is about 100 to 5000 and wherein the inner biologicallyacceptable silicone polymer matrix has microsealed compartmentsdistributed throughout, said microsealed compartments containing apharmaceutical in a hydrophilic solvent system consisting of water and20-70% polyethylene glycol, said microsealed compartments being formedby in situ cross-linking of the liquid silicone polymer after it isemulsified with hydrophilic solvent system containing thepharmaceutical, the pharmaceutical being diffusible through the innerbiologically acceptable silicone polymer matrix and biologicallyacceptable polymer container at a therapeutically effective constantrate when the microsealed pharmaceutical delivery device is in anaqueous environment, said hydrophilic solvent being non-diffusiblethrough the inner biologically acceptable silicone polymer matrix andbiologically acceptable polymer container.

A biologically acceptable silicone polymer matrix containing apharmaceutical in a hydrophilic solvent system is prepared as follows: 2parts of a 40% polyethylene glycol (molecular weight 380-420) in wateris saturated with 2 parts of ethynodiol diacetate at 37° C. by vigorousagitation for 10 minutes. To this mixture is added 6 parts of liquidsilicone polymer of the formula ##STR5## sold as Silastic Medical Grade382 Elastomer by Dow-Corning and this combination is stirred with amechanical mixer at 1000 rpm for 28 minutes. 0.015 Parts of across-linking agent (stannous octanoate is added to the combination andstirring is continued for 2 minutes. The combination is placed in asilicone rubber tubing (I.D. 3.18mm, O.D. 6.35mm sold by Dow-Corning asMedical Grade Silastic Tubing No. 601-365). This tubing is a siliconepolymer of the formula. ##STR6## The system is allowed to cross-link for1 hour and then the tubing is sectioned to provide pharmaceuticaldelivery devices with the desired amount of pharmaceutical. The ends ofthe sections may be sealed or left open and additional openings may bemade in the walls of the tubing to facilitate higher but still constantrates of release. This device releases 315.6 mcg/cm² /day of ethynodioldiacetate. Replacement of the ethynodiol diacetate with 2 parts of oneof the following pharmaceuticals provides the indicated release rate:

    ______________________________________                                                               Release                                                                       Rate                                                                          mcg/cm.sup.2 /day                                      ______________________________________                                        17α-acetoxy-11β-methyl-19-norpregn-4-ene-                          3,20-dione               51.89                                                Desoxycorticosterone acetate                                                                           55.1                                                 17-hydroxy-7β-methoxycarbonyl-3-oxo-17α-                           pregn-4-ene-21-carboxylic acid γ-lactone                                                         63.08                                                7α-acetylthio-17α-(2-carboxyethyl)-17β-                      hydroxyandrost-4-ene-3-one lactone                                                                     18.25                                                metronidazole            4.23                                                 ______________________________________                                    

The present invention encompasses a method of distributing apharmaceutical throughout a biologically acceptable silicone polymercomprising (a) emulsifying a mixture of a liquid biologically acceptablesilicone polymer and hydrophilic solvent system containing apharmaceutical and (b) in situ cross-linking of the liquid biologicallyacceptable silicone polymer to form a biologically acceptable siliconepolymer matrix, said biologically acceptable silicone polymer matrixhaving microsealed compartments of 10 to 200 microns throughout, saidmicrosealed compartments containing the pharmaceutical and thehydrophilic solvent system.

Preferably the present invention encompasses a method of distributing apharmaceutical throughout a biologically acceptable silicone polymercomprising

a. emulfisying a mixture of a biologically acceptable liquid siliconpolymer of the formula ##STR7## wherein R is alkoxy containing 1-7carbon atoms, alkyl containing 1-10 carbon atoms, or allyl and n =100-5000 with a pharmaceutical in a hydrophilic solvent system of 20-70%polyethylene glycol in water; and

b. in situ cross linking the biologically acceptable liquid siliconepolymer to form a biologically acceptable silicon polymer matrix havingmicrosealed compartments of 10- 200 microns throughout, said microsealedcompartments containing the pharmaceutical in the hydrophilic solventsystem.

Thus, the present invention encompasses an improvement in knownpharmaceutical delivery devices, the improvement comprising abiologically acceptable polymer matrix having 10-200 micron microsealedcompartments throughout, the microsealed compartments containing apharmaceutical in a hydrophilic solvent system, the improvementproviding for control of the release rate of the pharmaceutical as afunction of time.

A number of pharmaceutical delivery devices wherein a pharmaceutical isenclosed in a polymer are known. U.S. Pat. No. 3,279,996 describes animplantate comprising a pharmaceutical delivery device consisting of apharmaceutical enclosed in silicone polymer. The present device isparticularly distinguished in that the pharmaceutical in a hydrophilicsolvent system is contained in microsealed compartments distributedthroughout the silicone polymer matrix. U.S. Pat. No. 3,279,996describes in situ polymerization of a liquid silicone polymer containinga pharmaceutical in vivo, but there is no hydrophilic solvent to controlthe rate of pharmaceutical release or for the formation of microsealedcompartments. The presence of microsealed compartments was establishedby replacing the pharmaceutical with a hydrophilic dye and visuallyobserving with the aid of a microscope the location of the dye indiscrete microsealed pockets. It has also been observed thatpharmaceuticals which are highly soluble in silicone polymer such asethynodiol diacetate have a release rate from silicone rubberinplantates proportional to the square root of time (T^(1/2)) in theabsence of microsealed compartments containing a suitable hydrophilicsolvent. A silicone rubber capsule containing crystalline drug within asdescribed in U.S. Pat. No. 3,279,996 likewise has a rate of releaseproportional to T^(1/2) and has an inherent danger of an overdoseresulting from a ruptured capsule. No such danger exists with thepresent pharmaceutical delivery device.

U.S. Pat. No. 3,710,795 describes a pharmaceutical delivery devicecomprising an inner polymer matrix with crystalline pharmaceuticaldistributed throughout and an outer polymer membrane surrounding theinner polymer matrix. The present device is particularly distinct inthat the pharmaceutical in a hydrophilic solvent is contained inmicrosealed compartments throughout the inner polymer matrix. Thedelivery system described in U.S. Pat. No. 3,710,795 releasespharmaceutical at rates proportional to the square root of time(T^(1/2)) where as in the delivery system of the present invention therate of drug release may be altered from T^(1/2) to T⁰ (independent oftime) by adjusting the solubility characteristics of the hydrophilicsolvent system (Table I). The use of 30-60% polyethylene glycol resultsin a rate of release independent of time (T⁰) whereas the use of largerpercentages of polyethylene glycol results in a rate of releaseproportional to T^(1/2). Thus, in the present system the relationship ofthe rate of release to time may be controlled by selection of anappropriate solvent. It is also noted that the delivery devices of thepresent invention do not have to be surrounded by an outer membrane. Infact, up to 40% of the inner matrix may be exposed. Exposing the innermatrix advantageously increases the rate of pharmaceutical releasedwithout altering the relationship of the release rate to time, i.e. in aconstant rate delivery device exposure of the inner matrix results in ahigher but constant rate of release.

U.S. Pat. No. 3,545,439 describes pharmaceutical delivery devicesprepared by mixing the pharmaceutical with a liquid silicone rubber andthen in situ cross-linking the liquid silastic rubber at roomtemperature. The rate of pharmaceutical release profile from thesedevices is related to T^(1/2). The present devices are advantageous inthat the relationship between rate of release and time may be controlledas mentioned above.

The following examples are set forth to illustrate the present inventionand are not intended to limit the invention in spirit or in scope. Inthe following examples parts are given in parts by weight andtemperature is in degrees centrigrade unless otherwise stated.

EXAMPLE 1

2 Parts of a 40% polyethylene glycol (molecular weight 380-420) in waterissaturated with 2 parts of ethynodiol diacetate at 37° C. byvigorousagitation for 10 minutes. To this mixture is added 6 parts ofsilicone polymer of the formula ##STR8##sold as Silastic Medical Grade382 Elastomer by Dow-Corning and this combination is stirred with amechanical mixer at 1000 rpm for 28 minutes.0.015 Parts of across-linking agent (stannous octanoate is added to the combination andstirring is continued for 2 minutes. The combination is placed insilicone polymer tubing (I.D. 3.18 mm, O.D. 6.35 mm sold by Dow-Corningas Medical Grade Silastic tubing No. 601-365). This tubing is a siliconepolymer of the formula ##STR9##The system is allowed to set for 1 hourand the tubing is sectioned to provide pharmaceutical delivery deviceswith the desired amount of pharmaceutical.

EXAMPLE 2

The silastic tubing is removed from the biologically acceptable innerpolymer matrix and a molecularly bi-axially oriented, heat shrinkablepolyethylene film, of 2 mil thickness is embossed about the inner matrixby using conventional metal stamping practice. The silicone polymermatrixis then sandwiched between two pieces of the heat shrinkablepolyethylene in the embossed sections so that the matrix is completelyenveloped by thefilm. The film is then heat sealed and cut around theperiphery of the matrix. The enshrouded matrix is then heated for 3seconds at 300° F. resulting in shrinkage of the film and effecting atight and intimate contact of the film with the pahrmaceuticalcontaining silicone polymer matrix.

The heat shrunk polyethylene film may be partially removed to expose theinner polymer matrix to provide a somewhat higher but constant rate ofrelease.

EXAMPLE 3

An emulsion of 2 parts of a 40% polyethylene glycol (molecular weight380- 420) in water is saturated with 2 parts of a17α-acetoxy-11β-methyl-19-norpregn-4-ene-3,20-dione at 37° C. byvigorous agitation for 10 minutes. To this mixture is added 6 parts ofroom temperature vulcanizing silicone polymer sold as Silastic MedicalGrade 382 elastomer by Dow-Corning and this combination is stirred witha mechanical mixer at 1000 rpm for 28 minutes. 0.015 Partsof across-linking agent (stannous octoate) is added to the combinationandstirring is continued for 2 minutes. The resulting emulsion is placedinto heat shrinkable tubing composed of a copolymer of ethylene andvinyl acetate of 82 percent ethylene and 18 percent vinyl acetate. Thetubing isof the type rendered heat shrinkable by intermolecularcross-linking followed by molecular orientation as described earlier.The ends of the tubing may be sealed by heat sealing or by the insertionof plugs. The tubing is heat shrunk by exposure to air heated at 280° F.for 5-15seconds. The tubing may be cut into sections and the ends sealedor left unsealed.

EXAMPLE 4

Following the procedure set out in Example 2, a biologically acceptablesilastic polymer matrix containing 2 parts of progesterone in place ofethynodiol diacetate is enclosed with heat shrinkable rubberhydrochloridefilm 1 mil thick by enclosing pre-set the biologicallyacceptable silicone polymer matrix with molecularly orientated heatshrunk rubber hydrochloride film and heat shrinking at 300° F. for 5seconds.

EXAMPLE 5

Following the procedure in Example 1, a device containing17α-acetoxy-11β-methyl-19-norgregn-4-ene-3,20-dione is preparedby using2 parts of that compound in place of ethynodiol diacetate. This devicereleases 17α-acetoxy-11β-methyl-19-norpregn-4-ene-3,20-dione at a rateof 51.89 mcg/cm² /day.

EXAMPLE 6

Following the procedure in Example 1, a device containingdesoxycorticosterone acetate is prepared by using 2 parts of thatcompoundin place of ethynodiol diacetate. This device releasesdesoxycorticosteroneacetate at a rate of 55.1 mcg/cm² /day.

EXAMPLE 7

Following the procedure in Example 1, a device containing17-hydroxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactone is prepared by using 2 parts of that compound in place ofethynodiol diacetate. This device releases17-hydroxy-7β-methoxycarbonyl-3-oxo-17α-pregn-4 -ene-21-carboxylic acidγ-lactone at a rate of 63.08 mcg/cm² /day.

EXAMPLE 8

Following the procedure in Example 1, a device containing7α-acetylthio-17α-(2-carboxyethyl)17β-hydroxyandrost-4-en-3-one lactoneis prepared by using 2 parts of that compound in place of ethynodioldiacetate. This device releases7α-acetylthio-17α-(2-carboxyethyl)-17β-hydroxyandrost-4-en-3-one lactoneat a rate of 18.25 mcg/cm² /day.

EXAMPLE 9

Following the procedure in Example 1, a pharmaceutical delivery deviceis prepared from 6 parts of liquid silicone polymer sold under the tradenameof Silastic Medical Grade MDX-4 4210 by Dow-Corning and 1.9 part ofethynodiol diacetate and 0.1 part of mestranol in 2 part 40%polyethylene glycol (molecular weight 400) in water.

What is claimed is:
 1. a method for constructing a biologicallyacceptable silicone polymer matrix adapted for placement in siliconepolymer or ethylene/vinylacetate copolymer tubing having 10-200 micronmicrosealed compartments distributed throughout, said microsealedcompartments containing a pharmaceutical in a hydrophilic solvent systemimpermeable to said polymer tubing, comprising:a. emulsifying thehydrophilic solvent system of water and liquid polyethylene glycolcontaining the pharmaceutical and biologically acceptableroom-temperature Vulcanizing liquid polydimethylsiloxane siliconepolymer and b. in situ cross-linking the biologically acceptable liuqidsilicone polymer to form the biologically acceptable silicone polymermatrix with microsealed compartments throughout containingpharmaceutical and hydrophilic solvent system.